The present invention relates to a multilayer orodispersible tablet and to the process for preparing it.
The term “orodispersible tablet” means a tablet intended to be disintegrated or dissolved in the mouth, without chewing, on contact with saliva, in less than 60 seconds and preferably less than 40 seconds, forming a particle suspension that is easy to swallow.
The disintegration time corresponds to the time between the moment when the tablet is placed on the tongue and the moment that the suspension resulting from the disintegration or dissolution of the tablet is swallowed.
This type of tablet is described, for example, in documents EP 548 356, EP 636 364, EP 1 003 484, EP 1 058 538, WO 98/46215, WO 00/06126, WO 00/27357 and WO 00/51568.
Once swallowed, the particles of active substance release the active substance into the lower part of the gastrointestinal tract.
Owing to its ease of use, the orodispersible tablet is entirely suitable for ambulatory treatment, more particularly for certain patients and especially the elderly or young children, who have difficulties in swallowing such that they find it unpleasant, or even impossible, to ingest tablets or gel capsules, even with a simultaneous intake of liquid.
It is estimated that 50% of the population experiences such difficulties, with the possible consequence of the prescribed medicinal product not being taken and thus a major impact on the efficacy of the treatment (H. Seager, 1998, J. Pharm. Pharmacol. 50, 375-382).
These difficulties in swallowing are obviously exacerbated when several medicinal products need to be taken throughout the day, thus multiplying the number of intakes.
Orodispersible tablets comprising fixed combinations of active substances would represent a solution for improving the patient compliance with long-term treatments, in the case of chronic pathologies especially affecting the elderly or children.
Attempts to produce such tablets have already been made, for example by tableting a single mixture comprising both tableting excipients and active substances. However, these tablets have certain drawbacks, especially non-uniformity of the contents of each of the active substances, or a risk of incompatibility between the various components of the tablet, active substances or excipients.
Specifically, a first technical difficulty is that of obtaining uniformity of the contents of each active substance, throughout the forming process, in this instance the tableting of the powder mixture comprising all the components of the said tablet.
Powder mixtures are generally complex to control since they consist of several populations of active substances and excipients, each having its own size, density or shape characteristics.
This non-uniformity gives rise to an increased risk of segregation, which is reflected by gradual demixing of certain populations of particles, during storage or in the feed hopper of the tableting machine.
The final unit form then has a highly variable content of each of the active substances, and intrinsic hardness, disintegration or palatability characteristics that are significantly different within the same batch.
Meticulous selection of the populations of active substances and excipients is not sufficient to entirely eliminate this risk.
Moreover, other solutions, applicable to orodispersible tablets, have been proposed to improve the content uniformity, for example by the Applicant in patent application FR 03 01308 (as yet unpublished), but these are not entirely satisfactory for limiting the risks of incompatibility.
Specifically, a second technical difficulty in producing tablets comprising a combination of active substances is the choice of active substances and excipients that may be used together, on account of a risk of incompatibility between the active substances themselves or between an active substance and excipients, this risk increasing when the number of components present in the tablet is larger.
In order to reduce these risks of incompatibility, solutions have been proposed, especially via the preparation of multilayer tablets. Such tablets have been described for many years (Abrégé de Pharmacie Galénique [Abstract of Pharmaceutical Pharmacy], Le Hir, 3rd ed., p. 269, Evaluation of bilayer tablet machines—A case study. S. P. Li, M. G. Karth, K. M. Feld, L. C. Di Paolo, C. M. Pendharkar, R. O. Williams, Drug Dev. Ind. Pharm., 21 (5), 571-590 (1995)).
They are formed from at least two layers that adhere together via a surface.
Each layer of the tablet has its own composition, and is successively formed by a cycle of tableting, which limits both the risks of non-uniformity of content and of physicochemical incompatibility.
However, this type of tablet requires formulation adjustments to ensure cohesion of the various layers.
This aim is usually achieved by applying high compression forces, resulting in tablets with hardness values that are often much higher than 100 N, or by the presence of a binder in at least one of the layers of the tablet, in an amount that is effective for promoting adhesion between the layers.
Furthermore, the preparation of a multilayer tablet makes it necessary to repeat the application of compression forces on each powder mixture.
These conditions are therefore not favourable, either in the case of tablets intended to be disintegrated rapidly, or in the case of active substances requiring masking of their bitterness, via means such as polymer coating, that are known to be particularly sensitive to compression, and the use of which is incompatible with the application of high compression forces, which increases the risk of breaking the film.
This is why, at the present time, among the solid forms intended to be disintegrated in the mouth, the only multilayer tablets that exist are in the form of tablets or pastilles for sucking, for the administration of active substances with local action, limited to the buccal mucosae and the oropharynx and that do not require any taste masking other than the simple addition of sweeteners.
One known example of such tablets for sublingual administration is Solutricine® vitamin C sold in France by Theraplix, which is a three-layer tablet comprising tyrothrycin and ascorbic acid.
These multilayer tablets for sucking have a high level of hardness to ensure adhesion of the layers, and have a residence time in the oral cavity of several minutes, corresponding to the time during which the tablet gradually disintegrates.
The erosion and solubilization, the main mechanisms of disintegration of such tablet, then directly depend on the size of the tablet and its surface area in contact with the saliva.
As a result of the constraints they impose, the solutions proposed to date for formulating combinations of active substances therefore cannot be applied to orodispersible tablets, and even less so when the taste of the active substances used needs to be masked.
There is thus a real need for orodispersible tablets that allow the combination of various active substances, which are optionally coated, without having the drawbacks of non-uniformity of content or of incompatibility.
The Applicant has found, against all expectations, that it is possible to obtain a multilayer orodispersible tablet.